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Nat Commun. 2018 Oct 15;9(1):4260. doi: 10.1038/s41467-018-06607-1.

The fungal peptide toxin Candidalysin activates the NLRP3 inflammasome and causes cytolysis in mononuclear phagocytes.

Author information

1
Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knoell Institute, Beutenbergstrasse 11a, Jena, 07745, Germany.
2
Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Ismaninger Str. 22, München, 81675, Germany.
3
Program in Cell Biology, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1×8, Canada.
4
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology, 9000 Rockville Pike, Bldg 10 / Rm 11C102, Bethesda, MD, 20892, USA.
5
Institute of Immunology and Immunotherapy, Institute of Microbiology and Infection, University of Birmingham, Birmingham, B15 2TT, UK.
6
Institute of Neuropathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Breisacher Straße 64, Freiburg, 79106, Germany.
7
TranslaTUM, Center for Translational Cancer Research, Technische Universität München, München, 81675, Germany.
8
German Cancer Consortium (DKTK), Heidelberg, 69120, Germany.
9
German Center for Infection Research (DZIF), Munich, 81675, Germany.
10
Mucosal and Salivary Biology Division, King's College London Dental Institute, London, SE1 1UL, UK.
11
Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knoell Institute, Beutenbergstrasse 11a, Jena, 07745, Germany. bernhard.hube@leibniz-hki.de.
12
Friedrich Schiller University, Fürstengraben 1, Jena, 07743, Germany. bernhard.hube@leibniz-hki.de.

Abstract

Clearance of invading microbes requires phagocytes of the innate immune system. However, successful pathogens have evolved sophisticated strategies to evade immune killing. The opportunistic human fungal pathogen Candida albicans is efficiently phagocytosed by macrophages, but causes inflammasome activation, host cytolysis, and escapes after hypha formation. Previous studies suggest that macrophage lysis by C. albicans results from early inflammasome-dependent cell death (pyroptosis), late damage due to glucose depletion and membrane piercing by growing hyphae. Here we show that Candidalysin, a cytolytic peptide toxin encoded by the hypha-associated gene ECE1, is both a central trigger for NLRP3 inflammasome-dependent caspase-1 activation via potassium efflux and a key driver of inflammasome-independent cytolysis of macrophages and dendritic cells upon infection with C. albicans. This suggests that Candidalysin-induced cell damage is a third mechanism of C. albicans-mediated mononuclear phagocyte cell death in addition to damage caused by pyroptosis and the growth of glucose-consuming hyphae.

PMID:
30323213
PMCID:
PMC6189146
DOI:
10.1038/s41467-018-06607-1
[Indexed for MEDLINE]
Free PMC Article

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